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Protein kinase CK2 is important for the function of glioblastoma brain tumor initiating cells

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Abstract

Protein kinase CK2 is a ubiquitously expressed serine/threonine kinase composed of two catalytic subunits (α) and/or (α′) and two regulatory (β) subunits. The expression and kinase activity of CK2 is elevated in many different cancers, including glioblastoma (GBM). Brain tumor initiating cells (BTICs) are a subset of cells that are highly tumorigenic and promote the resistance of GBM to current therapies. We previously reported that CK2 activity promotes prosurvival signaling in GBM. In this study, the role of CK2 signaling in BTIC function was examined. We found that expression of CK2α was increased in CD133+ BTICs compared to CD133− cells within the same GBM xenolines. Treatment with CX-4945, an ATP-competitive inhibitor of CK2, led to reduced expression of Sox2 and Nestin, transcription factors important for the maintenance of stem cells. Similarly, inhibition of CK2 also reduced the frequency of CD133+ BTICs over the course of 7 days, indicating a role for CK2 in BTIC persistence and survival. Importantly, using an in vitro limiting dilution assay, we found that inhibition of CK2 kinase activity with CX-4945 or siRNA knockdown of the CK2 catalytic subunits reduced neurosphere formation in GBM xenolines of different molecular subtypes. Lastly, we found that inhibition of CK2 led to decreased EGFR levels in some xenolines, and combination treatment with CX-4945 and Gefitinib to inhibit CK2 and EGFR, respectively, provided optimal inhibition of viability of cells. Therefore, due to the integration of CK2 in multiple signaling pathways important for BTIC survival, CK2 is a promising target in GBM.

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Acknowledgements

We thank Dr. G. Yancey Gillespie and Catherine Langford of the UAB Brain Tumor Animal Models Core Facility (NIH P20CA151129) for assistance, and acknowledge the use of the UAB Rheumatic Diseases Core Center-Comprehensive Flow Cytometry Core (P30 AR048311 and P30 A127667). This work was supported by NIH grants R01CA194414 and R01CA1585340 (E.N.B.), T32NS048039 (A.L.R.), T32AI007051 (S.A.G.), R01CA138517 (S.E.N.) and R01CA1515122 (A.B.H.). Additional funding is from American Brain Tumor Association Discovery Grant (B.C.M.), William E. Cash Jr. Memorial Fund in Neuro-Oncology Research (B.C.M. and S.E.N.), Career Transition Award from the National Multiple Sclerosis Society TA3050-A-1 (G.P.M.), UAB Comprehensive Cancer Center (S.E.N.) and the UAB Brain Tumor SPORE Career Development Award Program via P20CA151129 (A.B.H.).

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Authors and Affiliations

  1. Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA

    Amber L. Rowse, Sara A. Gibson, Gordon P. Meares, Rajani Rajbhandari, Susan E. Nozell, Kory J. Dees, Anita B. Hjelmeland, Braden C. McFarland & Etty N. Benveniste

  2. Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 1918 University Blvd, MCLM 388, Birmingham, AL, 35294-0004, USA

    Braden C. McFarland

  3. Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 510, 20th Street South, FOT 1220D, Birmingham, AL, 35294-3412, USA

    Etty N. Benveniste

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  1. Amber L. Rowse
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  2. Sara A. Gibson
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Correspondence to Braden C. McFarland or Etty N. Benveniste.

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Rowse, A.L., Gibson, S.A., Meares, G.P. et al. Protein kinase CK2 is important for the function of glioblastoma brain tumor initiating cells. J Neurooncol 132, 219–229 (2017). https://doi.org/10.1007/s11060-017-2378-z

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